PROJECT SUMMARY/ABSTRACT Stimuli (cues) in the environment associated with reward can motivate normal behavior, bringing one in close proximity to valuable resources (i.e. food, water, mates); but they can also gain inordinate control over behavior, as is the case with addiction. The ability of reward cues to motivate both normal and maladaptive behavior occurs through Pavlovian learning processes. Thus, when a discrete cue is repeatedly paired with presentation of a reward, it can acquire the ability to act as a predictor, but can also acquire incentive motivational properties. For example, in addicts, cues that have been previously associated with the drug- taking experience acquire the ability to maintain drug-seeking behavior and instigate relapse, even when there is a strong desire to stop use. We have recently discovered that in rats there is considerable individual variation in the extent to which food cues are attributed with Pavlovian incentive motivational value (?incentive salience?) and this variation predicts how avidly they will later seek drugs and the propensity to relapse. Using a Pavlovian conditioning paradigm, rats can be classified as sign-trackers?those that attribute incentive salience to reward cues, or goal-trackers?those that assign only predictive value to reward cues. Thus, this animal model allows us to parse the incentive from the predictive properties of reward-associated cues and to elucidate the neural circuitry underlying these distinct forms of cue-reward learning. In the proposed studies we will exploit this natural variation in the propensity to attribute incentive salience to reward cues, using a uniquely heterogeneous population of rats. Further, we will use a novel molecular-genetic approach that uses viral vectors to express engineered artificial receptors (known as DREADD receptors), to examine how transiently modulating activity of specific brain circuits will alter the propensity to sign-track or goal-track. Specifically, the proposed studies focus on afferent systems to the paraventricular nucleus of the thalamus (PVT), a site that has gained increasing attention in the addiction literature, and has recently been shown to play a role in sign- vs. goal-tracking behavior. We will test the hypothesis that sign-tracking behavior, which is dopamine dependent, is mediated via subcortical processes including dopaminergic projections from the ventral tegmental area (VTA) to the PVT; and that goal-tracking behavior, which is dopamine-independent, is mediated via cortical ?top-down? afferents to the PVT. We will also examine how altering activity in these specific circuits will affect patterns of food- and drug-cue-induced neuronal activity throughout the brain in sign- trackers vs. goal-trackers. This work will lead to a better understanding of the neural mechanisms that go awry in psychopathologies like addiction, and has the potential to lead to novel therapeutic interventions.